I have a longstanding interest in hormonal signaling, particularly mechanisms employed by insulin. The long term goal of my research is to elucidate the molecular events that constitute the mechanism of action of insulin. I was interested in activation of receptors and studied a small peptide hormone to deduce its receptor-bound conformation. I studied the mechanisms of regulation of sodium transport by steroid and peptide hormones including insulin. My current research plan has evolved based on experiments 1 did that demonstrate that insulin can activate S6 phosphorylation in vitro. Thus, the objectives of my research during the next five years are to understand how the major insulin-stimulated S6 protein kinase, which we have recently purified, is regulated using antibodies and molecular cloning and then to use the enzyme as a probe to identify and purify molecules that regulate its activity in response to insulin. Subsequent studies will focus on the mechanisms of control of the regulatory molecules by insulin and insulin receptor. The mechanism of insulin action is a very difficult problem that has been a source of frustration to scientists for many years. Now we have finally begun to make significant progress in elucidating steps in this pathway. Particularly at this critical time, when new developments are occurring rapidly, I feel that this award will give me a greater opportunity to achieve my goals by allowing me to concentrate more of my time on my research on hormonal signaling.